The nuclear receptor (NR) superfamily of ligand regulated transcription factors has proven to be a rich source of targets for the development of therapeutics for a wide range of human diseases. The retinoic acid receptor-related orphan receptors (ROR?, ROR? and ROR?) regulate several physiological processes, including the circadian rhythm, glucose and lipid metabolism, and immune functions. ROR? is found in regions of the central nervous system (CNS) that are involved in processing of sensory information and components of the mammalian timing system (circadian clock genes), including the suprachiasmatic nuclei (SCN), retina, pineal gland, and bone. The ROR?-/- mouse phenotype has not yet been completely characterized. Selective small molecule modulators of ROR? are needed to compliment these efforts. The lack of tractable small molecule ligands that bind ROR? has hindered interrogation of the function of this receptor in vivo. Recently, dual ROR?/? ligands have been identified. Since, our labs have previously collaborated to identify and develop pan-ROR modulators, ROR?-selective agonists and inverse agonists, and ROR?-selective inverse agonists, we are well positioned to identify, characterize and develop ROR?-selective modulators. Given the receptors specific tissue distribution and important physiological functions, the identification of ROR?-selective small molecules would be a valuable chemical probe and pharmacological tool. Our goal is to optimize current pan scaffolds into ROR?-selective compounds with the appropriate pharmacodynamic (PD) and pharmacokinetic (PK) properties to provide ROR? probes to interrogate the function of the receptor in vivo and its role in the pathophysiology of disease. In order to achieve this goal, we propose the following Specific Aims: 1) Further develop and optimize ROR?-selective ligands with improved potency, selectivity and pharmacokinetic properties; 2) Characterize the pharmacology of these ROR?-selective compounds in vitro and in vivo. Accomplishment of these Aims will provide novel, first-in-class ligands that selectively modulate ROR? activity. These probes will be useful for the study of the receptors function in vivo in animal models of disease such as circadian rhythm and psychosis, eye disorders, as well as in age-related bone loss.